Intra-lesional Nivolumab Therapy for Limited Cutaneous Kaposi Sarcoma

Infection with Kaposi sarcoma herpesvirus (KSHV, or human herpesvirus-8 [HHV-8]) causes
Kaposi sarcoma (KS). These virally associated diseases occur more frequently in HIV-infected
individuals, but can also be found in HIV-uninfected population. Evolution of
immunosuppressive mechanisms presumably plays a permissive role in the development,
progression and recurrence of these virus-associated cancers and pre-cancers. Currently,
available treatment options for these lesions are imperfect.

The goal of this study is to determine whether intra-lesional injections of nivolumab can
enhance specific T cell responses in vitro and enhance activity against these
virus-associated lesions. Chronic viral infections generate "exhausted" CD8+ T cells with a
diminished capacity to produce cytokines and to lyse infected cells. The PD-1 (program
death-1)/PD-L1 (program death ligand-1) pathway implicated in the balance between immune
eradication and immune escape. This study will evaluate the safety, tolerability, and
potential benefits of injecting nivolumab into KS in HIV-infected and HIV-uninfected
individuals every 2 weeks for total of 4 doses. The investigators believe this mode of
treatment is feasible and tolerable by avoiding the systemic autoimmune adverse events caused
by systemic injection of nivolumab.

Inclusion Criteria:

- Histologically confirmed KS with active cutaneous disease and have less than 25
lesions in total. They must not have symptomatic visceral KS or asymptomatic pulmonary
KS.

Cohort A (safety): treatment-experienced KS Cohort B: treatment-naïve KS

- For HIV-infected patients: CD4>350 cells/mm3 and HIV-1 viral load <75 copies/mL).

- Patients must have measurable cutaneous KS disease, defined as: 1 or more marker
lesion that is bi-dimensionally measureable, and ≥0.5cm in shortest dimension. These
lesions must not have received previous local radiation, surgical, or intra-lesional
cytotoxic therapy that would prevent response assessment.

- Adequate organ function

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Exclusion Criteria:

- Prior systemic KS-directed treatments or investigational modalities ≤ 5 half-lives or
4 weeks, whichever is shorter, prior to starting study drug or who have not recovered
from side effects of such therapy to grade 1 or less.

- Hypersensitivity to nivolumab or any of its excipients

- Has a known additional malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer.

- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment

- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

- Active systemic immunosuppressive therapy

- The use of prednisone or equivalent 10mg or greater a day that cannot be discontinued
with more than 7 consecutive days of steroids within the prior 2 weeks.

- Prior organ allograft or allogeneic transplantation, if the transplanted tissue is
still in place.